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ToxSci Advance Access published online on September 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg232
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received June 10, 2003; accepted August 22, 2003
© 2003 Society of Toxicology

Carcinogenicity

Arsenic and Benzo[a]pyrene Differentially Alter the Capacity for Differentiation and Growth Properties of Primary Human Epidermal Keratinocytes

D. S. Perez 1, L. Armstrong-Lea 2, M. H. Fox 2, R. S. H. Yang 1, and J. A. Campain 1*

1 Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Colorado State University, Ft. Collins, CO 80523
2 Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO 80523

* To whom correspondence should be addressed. E-mail: julie.campain{at}colostate.edu.


  Abstract

Normal human epidermal keratinocytes (NHEK) have been chosen as an in vitro model to test the hypothesis that chemicals which alter or interfere in cellular differentiation will concomitantly induce growth perturbations and are, thus, potential carcinogens. In these studies, we have focused on two known skin carcinogens, arsenic and benzo(a)pyrene (BaP). Our results demonstrated that BaP inhibits terminal differentiation in NHEK, as measured by cross-linked envelope (CLE) formation, by up to 5.8-fold in control and 1.7-fold in calcium (Ca2+)-treated cells. In comparison, arsenic decreased CLE formation by 20-fold in control cells and 5.5-fold in Ca2+-treated NHEK. To characterize the effects of these agents on the growth rate and cell cycle distributions of NHEK, flow cytometric analysis was used. BaP at 2 µM increased proliferation rates by 29%. Altered cell-cycle distribution in BaP-treated cells indicated a more rapid progression through the cell cycle, possibly by a shortened G2 phase. In contrast, arsenic at 5 µM inhibited proliferation by 25%; growth arrest (9%) was also observed in NHEK treated with 2 mM Ca2+. Our findings suggest that, although both BaP and arsenic inhibit CLE production in NHEK, different mechanisms may be involved. Studies in progress will attempt to identify molecular markers involved in the observed chemical effects. These markers will facilitate a mechanistic understanding of how an altered balance between growth and differentiation may play a role in the transformation process in NHEK.

Key Words: Keratinocytes, Differentiation, Proliferation, Benzo[a]pyrene, Arsenic, Calcium .


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